Orlistat

Structural formula
General
Non-proprietary name	Orlistat
other names	Tetrahydrolipstatin (2 S ) -2-Formylamino-4-methylpentanoic acid- (1 S ) -1 - {[(3 S , 4 S ) -3-hexyl-2-oxo-4-oxetanyl] methyl} dodecyl ester ( IUPAC ) (all- S ) -2-Formylamino-4-methylpentanoic acid 1 - [(3-hexyl-2-oxo-4-oxetanyl) methyl] dodecyl ester Orlistatum ( Latin )
Molecular formula	C 29 H 53 NO 5
Brief description	White to almost white, crystalline powder
External identifiers / databases
CAS number 96829-58-2 EC number 639-755-1 ECHA InfoCard 100.167.400 PubChem 3034010 DrugBank DB01083 Wikidata Q424163
Drug information
ATC code	A08 AB01
Drug class	Anti-obesity
Mechanism of action	Lipase inhibitors
properties
Molar mass	495.73 g · mol -1
Physical state	firmly
Melting point	43 ° C
pK s value	no value within the physiological pH value
solubility	Practically insoluble in water , readily soluble in chloroform , very soluble in methanol and ethanol
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Orlistat is a medicinal substance for the treatment of obesity (overweight), which should be used in combination with a medically supervised reduction diet . It reduces - without curbing the appetite - the absorption of fat and thus the absorption of energy (see: Physiological calorific value ) from the intestine by inhibiting fat-breaking down enzymes . It is as good as not absorbed. The data so far show that (only) some of the patients can reduce their body weight by up to ten percent. Orlistat should therefore not be taken again if the patient has not lost five percent of his initial weight after twelve weeks of taking it.

Orlistat is semi-synthetically from the from Streptomyces toxytricini isolated lipstatin produced.

pharmacology

Pharmacodynamics

Orlistat inhibits specific and long-lasting fat-digesting enzymes ( lipases ) of the gastrointestinal tract . The therapeutic effect begins within the stomach and continues in the area of ​​the upper small intestine . Chemically, Orlistat binds covalently to the active center of gastric and pancreatic lipase ( pancreatic lipase ). As a result, these lipases are irreversibly inactivated and can no longer break down ( hydrolyze ) the dietary fats present in the form of triglycerides into absorbable free fatty acids and monoglycerides . As a result, digestion and absorption of up to 35% of the fats ingested with food are prevented, thus lowering serum cholesterol . This primarily results in a reduction in body weight, which secondarily improves glucose tolerance and increased blood pressure values ​​can decrease (see metabolic syndrome ). However, orlistat appears to be counterproductive in stimulating appetite.

Pharmacokinetics

Studies in normal and overweight subjects have shown that the active ingredient is only absorbed by the body to a very small extent. Plasma concentrations of unmetabolized orlistat were not measurable eight hours after oral ingestion of orlistat (<5 ng / ml). In most cases, at therapeutic doses, unmetabolized orlistat could only be detected sporadically and only in extremely low concentrations (<10 ng / ml or 0.02 μmol) in the plasma , whereby no accumulation could be detected . This suggests minimal resorption.

application areas

Orlistat is in conjunction with a mildly hypocaloric diet for the treatment of obese patients with a body mass index ( body mass index admitted BMI) ≥ 30 kg / m², or overweight patients (BMI ≥ 28 kg / m²) with accompanying, weight-dependent risk factors . Treatment with orlistat should be discontinued after 12 weeks if the weight loss is not at least 5% of the body weight at the start of the medication.

There are no clinical studies for use in children and adolescents under 18 years of age.

Contraindications and restrictions on use

Orlistat should not be used in

• Chronic malabsorption syndrome
• Cholestasis
• Pregnancy , lactation
• Hypersensitivity to orlistat
• Concomitant treatment with ciclosporin, warfarin or other oral anticoagulants .

Since weight loss in diabetes can be associated with improved metabolic control, patients taking an anti-diabetic drug should consult a doctor before starting therapy with orlistat, as the dosage of the antidiabetic drug may need to be adjusted.

Close medical monitoring should be carried out while taking medicines for the treatment of diabetes mellitus , as orlistat can affect the effectiveness of blood sugar-lowering drugs .

Patients with chronic kidney disease and / or dehydration are at increased risk that treatment with orlistat can lead to hyperoxaluria and oxalate nephropathy , which sometimes leads to kidney failure.

Side effect / adverse drug effects

Gastrointestinal side effects are mainly and very frequently observed: steatorrhea (fatty stools), unpleasant stool smear (anal leakage) , increased intestinal peristalsis , urge to defecate and increased bowel movements and flatulence (intestinal winds). Serum levels of fat-soluble vitamins decrease with orlistat as a result of impaired absorption by the drug. Decreased values ​​are documented for vitamins D , E and β-carotene . Normal ranges are not fallen below on average, however, in individual cases pathologically lowered values ​​can occur. Under certain circumstances, vitamin supplements should be added to accompany therapy . After 21 suspected cases of, in rare cases serious, liver-damaging effects for the 120 mg dose in the period from August 2009 to January 2011 and 9 from May 2007 to January 2011 for the 60 mg dose, the European Medicines Agency are considering the need to re-evaluate Orlistat.

A study published in December 2012 warns that orlistat may use other drugs, e.g. B. Acetylsalicylic acid (aspirin) or cytostatics have a negative effect. The number of adverse drug reactions has increased since the drug became available without a prescription.

Clinical studies

In the previously submitted placebo-controlled four two-year studies and in a four-year study, which was treating each with a power-reduced (low-calorie) diet combined. The collected results from these studies show that the twelve-week combination treatment led to a weight loss of at least 5% of their body weight in comparison to the start of treatment in 37% of the treated patients and in 19% of the placebo patients. If the treatment is continued, the subjects lose even more weight: 49% of the patients treated with orlistat and 40% of the patients treated with placebo lost a further 10% of their body weight or more in the first year compared to the start of use. Conversely, without initial treatment success, there is rarely such a significant weight loss during the first twelve weeks, even later.

Overall, the proportion of patients who had lost 10% of their initial body weight or more while taking 120 mg orlistat in combination with a hypocaloric diet was 20%, compared with 8% for placebo. On average, the difference in weight loss achieved between the drug and placebo groups was 3.2 kg.

The weight loss after one year of treatment with a weight-reducing diet and orlistat is significantly better maintained in a second year than with the administration of a placebo while maintaining the orlistat administration and a weight-maintaining diet. The weight gained again in the second year is on average 3.2 (orlistat) instead of 5.6 kg (placebo), with a previous average weight loss of 8.8 kg (orlistat) or 5.8 kg (placebo) in the first Year.

In clinical trials, a third of patients stopped orlistat treatment prematurely.

Additional data from clinical studies suggest the possibility that the weight loss achieved with orlistat use may delay the occurrence of adult diabetes ( type II diabetes mellitus ). In principle, all risk factors associated with obesity can be positively influenced: lowering total cholesterol , lowering LDL and increasing HDL cholesterol, lowering fasting blood sugar, lowering insulin concentrations in the serum , falling systolic and diastolic blood pressure values . Results from long-term studies on the influence of cardiovascular complications ( heart attack , stroke ) and mortality are still lacking.

Another study showed that with a combination treatment of orlistat, hypocaloric diet, vitamin supplementation and physical exercise , weight loss comparable to that of adults can also be achieved in the problem group of obese adolescents (under study conditions). However, an increased incidence of bone fractures with orlistat appears worrying.

Meta-analysis

In a meta-analysis published in 2007, which included 16 double-blind, randomized, and placebo-controlled studies with an observation period of one year or longer, people treated with orlistat showed a weight loss of 2.9 kg compared to placebo-takers (a 5% decrease over placebo Weight reduction in 21%, a 10% in 12% of the patients). The incidence of diabetes mellitus and plasma concentrations of total cholesterol were reduced, as was those of LDL (by 0.27 mmol / L). Systolic and diastolic blood pressure were reduced by an average of 1–2 mmHG, and glycemic control improved. As an undesirable effect, gastrointestinal side effects were increased compared to placebo and the plasma concentrations of HDL were slightly reduced.

Commercial preparations

Xenical 120 mg requires a prescription in Germany (approved since 1998), Austria and Switzerland - as in many other countries . H. only available by prescription . In Greece, Australia and many parts of Asia, the drug is sold in pharmacies without a prescription.

In February 2007, the Food and Drug Administration (FDA) and in January 2009 the European Commission granted approval for an over-the-counter formulation of 60 mg orlistat with the trade name Alli . The manufacturers Hexal AG and Ratiopharm brought out generic drugs with the same drug substance, which are sold under the drug name Orlistat . In Austria, test purchases showed that the drug is often sold in pharmacies that deviate from the indication and disregard the contraindications. There are therefore isolated considerations as to whether the over-the-counter status of orlistat is sufficiently safe (see section Side Effects / Adverse Drug Effects ).

Web links

• Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Orlistat
• "Xenical" slimming product at the North Rhine-Westphalia consumer center

Individual evidence

1. ↑ ^{a b c} FDA Label Xenical (PDF; 320 kB)
2. ↑ Entry on Orlistat. In: Römpp Online . Georg Thieme Verlag, accessed on December 28, 2014.
3. ↑ ^{a b} Orlistat data sheet , ≥98%, solid from Sigma-Aldrich , accessed on February 19, 2013 ( PDF ).
4. ↑ ^{a b c d e} Xenical: Summary of the product characteristics (information for healthcare professionals) (PDF; 207 kB), European Medicines Agency , as of May 2009.
5. ↑ M. Ellrichmann, M. Kapelle u. a .: Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1- (7-36) -amide-1, cholecystokinin, and peptide YY concentrations. In: The Journal of clinical endocrinology and metabolism. Volume 93, Number 10, October 2008, pp. 3995-3998, doi: 10.1210 / jc.2008-0924 . PMID 18647814 .
6. ↑ Contraindications (contraindications) of orlistat. In: 121doc.com. Retrieved August 26, 2017 . 
7. ↑ Sjöström, L. et al. (1998): Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. In: The Lancet . Vol. 18, pp. 167-172 PMID 9683204
8. ↑ European Medicines Agency starts review of orlistat-containing medicines - Evidence relating to very rare cases of liver injury to be considered in depth (PDF; 59 kB), press release of September 22, 2011 (English).
9. ↑ D. Xiao, D. Shi et al. a .: Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs. In: Biochemical Pharmacology . Volume 85, Number 3, February 2013, pp. 439-447, doi: 10.1016 / j.bcp.2012.11.026 . PMID 23228697 .
10. ↑ Pharmacy researcher finds most popular weight-loss drug strongly alters other drug therapies , press release from the University of Rhode Island, Kingston, December 10, 2012.
11. ↑ L. Sjöström, A. Rissanen u. a .: Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. In: Lancet. Volume 352, Number 9123, July 1998, pp. 167-172, PMID 9683204 .
12. ↑ MH Davidson, J. Hauptman et al. a .: Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. In: JAMA. Volume 281, Number 3, January 1999, pp. 235-242, PMID 9918478 .
13. ↑ S. Rössner, L. Sjöström u. a .: Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. In: Obesity research. Volume 8, Number 1, January 2000, pp. 49-61, doi: 10.1038 / oby.2000.8 . PMID 10678259 .
14. ↑ L. Karhunen, A. Franssila-Kallunki and a .: Effect of orlistat treatment on body composition and resting energy expenditure during a two-year weight-reduction program in obese Finns. In: International journal of obesity and related metabolic disorders. Volume 24, Number 12, December 2000, pp. 1567-1572, PMID 11126207 .
15. ↑ ^{a b} J. S. Torgerson, J. Hauptman u. a .: XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. In: Diabetes care. Volume 27, Number 1, January 2004, pp. 155-161, PMID 14693982 . Full text
16. ↑ Davidson MH, Hauptman J, DiGirolamo M, et al. : Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial . In: JAMA . 281, No. 3, January 1999, pp. 235-42. PMID 9918478 .
17. ↑ Padwal R, Li SK, Lau DC: Long-term pharmacotherapy for obesity and overweight . In: Cochrane Database Syst Rev . No. 3, 2004, p. CD004094. doi : 10.1002 / 14651858.CD004094.pub2 . PMID 15266516 .
18. ↑ JP Chanoine, S. Hampl et al. a .: Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial. In: JAMA. Volume 293, Number 23, June 2005, pp. 2873-2883, doi: 10.1001 / jama.293.23.2873 . PMID 15956632 . Full text
19. ↑ Diana Rucker, Raj Padwal, Stephanie K Li, Cintia Curioni, David CW Lau: Long term pharmacotherapy for obesity and overweight: updated meta-analysis . In: BMJ . 335, 2007, pp. 1194-1199. doi : 10.1136 / bmj.39385.413113.25 .
20. ↑ Pharmainformation 23/1, February 2008
21. ↑ FDA Approves Orlistat for Over-the-Counter Use February 7, 2007.
22. ↑ Orlistat: Soon also without a prescription . ( Memento of February 24, 2014 in the Internet Archive ) Pharmaceutical newspaper online, January 21, 2009.
23. ↑ Alli slimming products are too easy to get. June 22, 2011, accessed January 10, 2012 . 
24. ↑ Pharmacies: Purchasing from Alli - 16 pharmacies tested. June 14, 2011, accessed January 10, 2012 . 
25. ↑ Questionable dispensing of slimming products in pharmacies. June 22, 2011, accessed January 10, 2012 . 
26. ↑ Baumgärtel, C .: Orlistat - over-the-counter delivery, p. 16, Christoph Baumgärtel. (PDF; 8.6 MB) August 1, 2011, archived from the original on December 26, 2015 ; Retrieved January 11, 2012 . 

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